CTBP1

Chr 4AD

C-terminal binding protein 1

Also known as: BARS, HADDTS

NCBI Gene: 1487 ENSG00000159692 UniProt: Q13363 OMIM: 602618

CTBP1 encodes a transcriptional corepressor with dehydrogenase activity that controls Golgi structure and brown adipose tissue differentiation. Mutations cause hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.98), reflecting its critical role in development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that binds to the C-terminus of adenovirus E1A proteins. This phosphoprotein is a transcriptional repressor and may play a role during cellular proliferation. This protein and the product of a second closely related gene, CTBP2, can dimerize. Both proteins can also interact with a polycomb group protein complex which participates in regulation of gene expression during development. Alternative splicing of transcripts from this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.281 OMIM phenotype

Clinical Summary— CTBP1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 144 VUS of 371 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.28LOEUF

pLI 0.984

Z-score 3.60

OE 0.06 (0.02–0.28)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.31Z-score

OE missense 0.45 (0.39–0.52)

126 obs / 282.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.28)

0≤0.351.4

Missense OE?0.45 (0.39–0.52)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 1 / 17.0Missense obs/exp: 126 / 282.5Syn Z: 0.02

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCTBP1-related hypotonia, ataxia, developmental delay, and tooth enamel defect syndromeLOFAD

This gene — mechanism propensity

0.4389th %ile

GOF

0.5465th %ile

LOF

0.71top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.28

DN1 literature citation

Literature Evidence

DNDecreased complex I and IV activities in skeletal muscle of our patient suggests that BAX expression is altered by mutated CtBP1, with the c.991C>T p.(Arg331Trp) variant acting in a dominant-negative mechanism to disrupt mitochondrial function.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 28955726 ↗

ClinVar Variant Classifications

371 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS144

Likely Benign188

Benign13

Conflicting8

Pathogenic

Likely Pathogenic

144

VUS

188

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	1	0	0	1
VUS	7	122	12	3	144
Likely Benign	0	11	71	106	188
Benign	0	0	9	4	13
Conflicting	—				8
Total	7	135	92	113	355

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

148 pathogenic / likely-pathogenic (of 163) ClinVar copy-number / structural variants overlap CTBP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →